Targeting cell death signalling in cancer: minimising ‘Collateral damage’

Abstract

Targeting apoptosis for the treatment of cancer has become an increasingly attractive strategy, with agents in development to trigger extrinsic apoptosis via TRAIL signalling, or to prevent the anti-apoptotic activity of BCL-2 proteins or inhibitor of apoptosis (IAP) proteins. Although the evasion of apoptosis is one of the hallmarks of cancer, many cancers have intact apoptotic signalling pathways, which if unblocked could efficiently kill cancerous cells. However, it is becoming increasing clear that without a detailed understanding of both apoptotic and non-apoptotic signalling, and the key proteins that regulate these pathways, there can be dose-limiting toxicity and adverse effects associated with their modulation. Here we review the main apoptotic pathways directly targeted for anti-cancer therapy and the unforeseen consequences of their modulation. Furthermore, we highlight the importance of an in-depth mechanistic understanding of both the apoptotic and non-apoptotic functions of those proteins under investigation as anti-cancer drug targets and outline some novel approaches to sensitise cancer cells to apoptosis, thereby improving the efficacy of existing therapies when used in combination with novel targeted agents.

TXNIP overexpression suppresses proliferation and induces apoptosis in SMMC7221 cells through ROS generation and MAPK pathway activation

“…2B and C). It has been confirmed that apoptosis could be induced through an intrinsic or extrinsic pathway (30)(31)(32), and activation of the caspase cascade was also involved in apoptosis (33). Only when caspase is cleaved can the activation of caspase occur.…”

Molecular mechanisms of neoplasia

“…Jest to możliwe dzięki wydzielaniu proapo-effectiveness of current therapies. This is possible due to the extrinsic induction of apoptosis by TRAIL signalling or inhibition of the antiapoptotic activity of Bcl-2 protein or IAP protein [43,44].…”

“…Szczegółowe poznanie ścieżek apoptotycznych i antyapoptotycznych oraz zrozumienie funkcji białek regulatorowych zaangażowanych w te szlaki pozwala na uwrażliwienie komórek nowotworowych na apoptozę, a tym samym poprawę skuteczności obecnych terapii. Możliwe jest to dzięki zewnątrzpochodnemu wywoła-niu apoptozy poprzez sygnalizację TRAIL lub zahamowanie antyapoptotycznej aktywności białka Bcl-2 lub białka IAP [43,44].…”

Targeting Apoptosis Signalling in Cancer: How Decreasing BAK Phosphorylation via BMX Inhibition Increases Sensitivity to Cytotoxic Drugs

“…Drugs approved for clinical use as well as many in the development pipeline aim to alter apoptotic signalling outcome or to trigger initiation of apoptosis, for example SMAC mimetics or BH3 mimetic Venetoclax respectively. However, these approaches have not been without their complications with both ontarget and off-target dose limiting toxicity reported, as well as the development of drug-induced resistance (reviewed in [2]). Despite the exciting progress that has been made in understanding and targeting the complex pathways that commits a cell to die by apoptosis, it is becoming increasingly clear that simply characterising the effector pathways is not enough [2].…”

“…However, these approaches have not been without their complications with both ontarget and off-target dose limiting toxicity reported, as well as the development of drug-induced resistance (reviewed in [2]). Despite the exciting progress that has been made in understanding and targeting the complex pathways that commits a cell to die by apoptosis, it is becoming increasingly clear that simply characterising the effector pathways is not enough [2]. Understanding the regulatory pathways and checkpoints at the crucial commitment points that trigger these executioner cell death pathways is equally important and could be the key to enable successful modulation of death pathways that determine cell fate.…”